Negative symptoms of schizophrenia are characterized by affective flattening, alogia, avolition, and anhedonia and are often nonresponsive to antipsychotic therapy. Because negative symptoms are predictive of poor occupational and social functioning, as well as poor global outcomes, numerous studies evaluating adjunct therapy to antipsychotics have been conducted.

This review article focuses on the use of the antidepressant mirtazapine as adjunct therapy to antipsychotics for the treatment of negative symptoms of schizophrenia.

A literature search of the MEDLINE database (from inception-March 2011) identified eight relevant articles: six were randomized, double-blind, placebo-controlled trials, and two were open-label trials. Of the six randomized trials reviewed, four studies assessed add-on mirtazapine to second-generation antipsychotics, whereas two studies examined add-on mirtazapine to first-generation antipsychotics. Five of the six randomized trials supported the use of mirtazapine for negative symptoms of schizophrenia. Of the two open-label trials, one naturalistic study demonstrated that mirtazapine add-on therapy to clozapine was not associated with improvements in negative symptoms; however, this study focused primarily on improvements in cognition, not negative symptoms. An open-label extension phase to a randomized controlled trial showed that mirtazapine continued to produce significant improvement in negative symptoms over a longer duration of time, when added to first-generation antipsychotic therapy.

Overall, mirtazapine appears to be well tolerated and associated with few drug interactions. Although adjunct mirtazapine to antipsychotics has been shown to be effective at doses of 30 mg/day in most of the trials, limitations of these studies include short study duration and small sample sizes. To improve generalizability, larger multicenter studies with broader inclusion criteria should be conducted. In addition, studies of longer duration that use different mirtazapine dosages are needed to further assess the benefits of mirtazapine for negative symptoms of schizophrenia